The Mount Sinai Alzheimer Disease Research Center (MSADRC) continues its historic success in research by using its unprecedented resources and expertise to seize opportunities for innovative approaches to understand, treat, and ultimately prevent the earliest signs of cognitive loss due to Alzheimer's disease (AD) and other causes of dementia. We have conducted critical basic translational and clinical studies to characterize cognitive loss and dementia in the elderly. We have used the National Alzheimer's Project Act (NAPA) as a road map to focus our established strengths. We continue our commitment to therapeutic development with innovative and powerful systems biology approaches to establish networks that can identify new targets and select trial ready candidates through pharmacological repurposing and by using the novel opportunity offered by our role in the international stem cell consortium, to develop neural progenitors, approaches to find unique models for therapeutic targets. We will develop a trial ready registry of non- demented elders who are informed and eager to participate in prevention studies. We will expand our characterization of racially and ethnically diverse elders currently underrepresented in research, and ensure the opportunity for them to participate in clinical research fully, including genetic analysis, biomarker studies, and clinical trials. We will continue to collect brains from our well-characterized clinical populations and focus our efforts on the pathology associated with the transition from normal aging and cognitive impairment. Contributing to National Alzheimer's Coordinating Center resources with clinical, neuropathological, and neuroimaging data will be continued as well as our commitment to provide the National Cell Repository for AD with samples for every eligible participant in our cohort. In keeping with the recommendations of NAPA and the 2013 AD-Related Dementias Research Workshop to include in the study of AD- related disorders a specific focus on the contribution of vascular risks, we will build on our expertise by proposing 3 projects that focus on the intersection of type 2 diabetes (T2D) one of the most common comorbidities of the at risk age group of AD. In Project 1, we will characterize cognitive loss and dementia in T2D individuals, examining markers of AD and insulin resistance including inflammation and cerebrovascular disease to identify the individual contribution and interactive roles of each pathogenetic factor. Minority participation will be a major feature of ths project to assure that our findings are applicable to the most applicable and understudied individuals. In Project 2, our well-characterized participant cohorts and animal models will be used with stem cell technology to identify the contribution of insulin resistance through cell types. In project 3, we examine the effects of T2D and AD on angiogenesis and angiogenic complexes. Together these efforts are aimed at identifying targets for intervention and prevention of AD. The resources of the cores and opportunities of the projects support the multidisciplinary studies of the widest community of researchers in cognitive loss and dementia.